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Journal of Clinical Oncology, Vol 23, No 33 (November 20), 2005: pp. 8371-8379 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.00.9969 Ifosfamide, Carboplatin, and Etoposide With Midcycle Vincristine Versus Standard Chemotherapy in Patients With Small-Cell Lung Cancer and Good Performance Status: Clinical and Quality-of-Life Results of the British Medical Research Council Multicenter Randomized LU21 TrialFrom the Medical Research Council Clinical Trials Unit, London; the Christie and Wythenshawe Hospital National Health Service Trusts, Manchester; and the Clatterbridge Hospital, Bebington, United Kingdom Address reprint requests to Richard Stephens, Medical Research Council Clinical Trials Unit, 222 Euston Rd, London NW1 2DA, United Kingdom; e-mail: rs{at}ctu.mrc.ac.uk
PURPOSE: Ifosfamide, carboplatin, etoposide, and vincristine, alone and in combination, are highly active against small-cell lung cancer (SCLC). This trial was designed to investigate whether survival could be improved by a regimen of all four drugs (ICE-V) compared with standard chemotherapy in patients with SCLC and good performance status, and to assess the patients’ quality of life (QL). PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of either ICE-V at 4-week intervals without dose reduction or standard chemotherapy administered according to local practice. The recommended standard control regimens were cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide. RESULTS: A total of 402 patients were randomly assigned, and 350 (87%) patients have died. Overall survival was longer in the ICE-V group (hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P = .0049), median survival was 15.6 months in the ICE-V group and 11.6 months in the control group, and 2-year survival rates were 20% and 11%, respectively. There was no evidence that the relative survival benefit for ICE-V was less in extensive-stage than in limited-stage patients. An increased rate of septicemia was reported in the ICE-V group (15% v 7% in the control group), but this did not result in an increase in reported treatment-related deaths (four patients [2%] in both groups). The findings on QL were broadly similar in both groups, with some benefit in favor of ICE-V. CONCLUSION: Compared with standard chemotherapy, the ICE-V regimen improves overall survival without QL penalties, despite an increased but manageable level of toxicity.
There is general agreement that patients with small-cell lung cancer (SCLC) and good performance status should be offered chemotherapy and when indicated, radiotherapy, aimed at prolonging survival and achieving a proportion of cures.1 In 1996, when the current trial was planned and activated, there was interest in the novel combination of ifosfamide with mesna, carboplatin, and etoposide (ICE) with or without midcycle vincristine (V). All four of the ICE-V drugs were known to be highly active against SCLC.1-4 The use of carboplatin avoids the nephrotoxicity, neurotoxicity, and ototoxicity associated with cisplatin, and carboplatin can be substituted for cisplatin without survival detriment or the fluid loading needed with cisplatin, which can be problematic in lung cancer patients.5,6 Phase II studies of ICE and ICE-V, followed by thoracic and prophylactic cranial radiotherapy when clinically indicated, in patients with good performance status and limited-stage (LS) or extensive-stage (ES) SCLC, reported complete response rates in excess of 50% and 2-year survival rates ranging from 24% to 33% for LS and 14% to 23% for ES.2,3,7,8 In contrast, 2-year survival rates with nonplatinum chemotherapy were approximately 15% in patients with LS disease, observed in previous trials including those conducted by the Medical Research Council Lung Cancer Working Party when the current trial was planned.9,10 A phase II study showed that dose-intensity with ICE-V could be kept high if dose reduction was avoided, but dose delay was permitted in the management of toxicity.4,7 In the study, which involved 42 patients, 74% received all six protocol cycles of ICE-V, 89% of the possible maximum number of cycles were administered (all without dose reduction), and only 17% of cycles were delayed because of toxicity. There were three deaths associated with treatment-related neutropenia. In studies of potentially curative chemotherapy, the measurement of quality of life (QL) is important because of the need to balance the expected impact on QL of treatment toxicity against prolongation of survival. Two widely used QL instruments in lung cancer trials are the Rotterdam Symptom Checklist (RSCL)11 modified to include additional lung cancer specific items, and the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30)12 plus lung cancer module (LC13).13 However, because these instruments had not been compared previously in a randomized fashion, this trial represented an opportunity to compare them in terms of compliance and ability to detect differences between regimens to guide the selection of QL instruments in future trials. The present randomized trial was conducted in patients with SCLC and good performance status to determine whether survival could be improved by administering ICE-V without dose reduction compared with standard-practice chemotherapy; to compare these two chemotherapy policies in terms of adverse effects of treatment and QL; and to compare the RSCL (with the additional lung cancer items) and the EORTC QLQ-C30 (plus LC13) questionnaires.
Main Eligibility Criteria Eligible patients had previously untreated, histologically confirmed SCLC of any stage; good performance status (WHO grade 0 to 2)14; plasma alkaline phosphatase, ALT or AST, sodium, and lactate dehydrogenase all normal (if disease extensive), or no more than one of them abnormal (if disease limited) in line with the definition of good prognosis developed by Cerny et al,15 and subsequently validated by Rawson and Peto,16 as well as serum creatinine or urea normal with creatinine clearance or glomerular filtration rate more than 65 mL/min; and full blood count normal. Female patients were not pregnant, were not of childbearing potential, or were using adequate contraception. Local ethics committee approval of the protocol and individual patient written consent were required.
Treatment Allocation Patients randomly assigned to the ICE-V regimen were prescribed six cycles of chemotherapy administered at 4-week intervals as follows: day 1, ifosfamide 5 g/m2, 24-hour infusion with mesna, carboplatin 300 mg/m2, and etoposide 120 mg/m2 by intravenous (IV) infusion; day 2, etoposide 120 mg/m2 by IV infusion; day 3, etoposide 240 mg/m2 orally; and day 14, vincristine 1.0 mg/m2 by IV injection. Patients randomly assigned to standard chemotherapy were prescribed six cycles of chemotherapy at 3-week intervals. On joining the trial, centers were asked which standard regimen they used. The recommended regimens were cyclophosphamide, doxorubicin, and etoposide (CDE) and cisplatin and etoposide (PE). The CDE regimen was day 1, cyclophosphamide 1 g/m2 and doxorubicin 40 mg/m2 by IV injection plus etoposide 120 mg/m2 by IV infusion; day 2, etoposide 120 mg/m2 by IV infusion; and day 3, etoposide 240 mg/m2 orally. The PE regimen was day 1, cisplatin 80 mg/m2 and etoposide 120 mg/m2 by IV infusion; day 2, etoposide 120 mg/m2 by IV infusion; day 3, etoposide 240 mg/m2 orally. However, other standard regimens were also permitted. In both treatment groups, it was recommended that a cycle of chemotherapy only be administered if the total WBC count was more than 3 x 109/L, the neutrophil count more than 1.5 x 109/L, and the platelet count more than 100 x 109/L, and there was no evidence of severe toxicity. In the ICE-V group, the recommendation for the management of myelotoxicity followed the strategy used in the phase II studies,4,7,8 whereby the cycle was delayed and administered at full doses when the above conditions were met, rather than reducing doses. In the control group it was recommended that drug dosages be modified in accordance with local practice. In both groups, patients with disease limited to the soft tissues of one hemithorax and the ipsilateral and contralateral scalene, lower cervical, and mediastinal lymph nodes at random assignment were offered thoracic radiotherapy after chemotherapy, and those achieving a complete response were offered prophylactic cranial irradiation; details were decided by the local radiation oncologist.
Reports and Investigations
Statistical Design and Methods
Duration of survival was calculated from the date of random assignment to the date of death as a result of any cause. At the time of the analysis, survivors were censored at the date they were last known to be alive. The log-rank test was applied to compare the Kaplan-Meier curves for overall survival. The
QL data for the two treatment groups were compared at 3 and 6 months from random assignment. To maximize use of available data, common symptom items in both instruments were identified and combined for the analysis. The comparison was based on symptoms reported by more than 20% of patients as moderately/quite a bit or very much at baseline, plus common adverse effects from chemotherapy, such as loss of hair, sore mouth, tingling of hands or feet, nausea, vomiting, and diarrhea; activities of daily living, assessed only by the RSCL and converted to a 5-point functional impairment scale18; overall QL, scored as 1 (excellent) to 7 (extremely poor); and anxiety and depression (the score from the HADS subscales were categorized using the standard cut-offs of 0 to 7 for normal, 8 to 10 for borderline, 11 to 21 for case).16 The standard All analyses were done on an intention-to-treat basis except for the analysis for response, which was restricted to all patients who received at least one cycle of chemotherapy treatment. All P values are two sided.
Role of the Funding Source
Patients Between March 1996 and February 2002, 402 patients (203 ICE-V; 199 C) were randomly assigned from 37 centers in the United Kingdom and Ireland (Fig 1). The two groups were well matched at baseline (Table 1).
Treatment Received In the C group, 153 patients were treated with CDE, 27 were treated with PE, and 16 were treated with other chemotherapy (eight with cyclophosphamide, doxorubicin, vincristine, and etoposide; four with ICE; four with alternating cyclophosphamide, doxorubicin, and vincristine, and PE). The remaining three patients had no chemotherapy (one died shortly after random assignment, one experienced disease progression shortly after random assignment, and one was found not eligible after random assignment). The number of cycles received in the ICE-V and C groups were similar (Table 2): 75% of ICE-V and 81% of C patients received four or more cycles. The commonest reason for stopping chemotherapy early in both treatment groups was death, progressive disease, or toxicity. Nineteen percent of cycles in ICE-V and 20% of cycles in C were delayed; the commonest reasons were neutropenia or other hematologic toxicity. Drug doses were modified in 22% of cycles in the ICE-V group; the commonest modification was the removal of vincristine (in 11% of cycles), compared with 9% of cycles in the CDE group and 16% of cycles in the PE group. For all regimens, neutropenia was the major reason for the modification.
After chemotherapy, thoracic radiotherapy was administered as part of primary treatment to 119 (71%) of the 167 ICE-V patients and 117 (70%) of the 166 C patients with limited disease. Eighty-one patients (40%) in the ICE-V group and 91 patients (46%) in the C group had prophylactic cranial irradiation. A total of 55 (27%) ICE-V and 46 (23%) C patients received second-line chemotherapy. Overall, patients in the ICE-V group required on average one more night in the hospital than the C group (mean, 16.8 nights ICE-V; 15.8 nights C); the main difference occurred between 3 and 6 months from random assignment when the ICE-V patients were continuing chemotherapy but the C group had stopped.
Adverse Effects
QL After the baseline assessments, 202 patients (102 ICE-V and 100 C) were randomly assigned to complete the HADS plus RSCL, and 200 patients (101 ICE-V and 99 C) were randomly assigned to complete the HADS plus the EORTC QLQ-C30 + LC13. Compliance with completion of QL assessments (an average of all the measures) at baseline, and 3 and 6 months was 84%, 67%, and 54% in the ICE-V group, and 90%, 80%, and 53% in the C group, respectively. At baseline, QL was similar across the two treatment groups, and most patients had little or no functional impairment. Nine symptoms fulfilled the criteria for inclusion in the analysis. The item decreased sexual interest, which was only reported on the RSCL, was included because of its high prevalence (41%). The between-treatment comparisons at 3 and 6 months of the 10 commonest symptoms, six adverse effects from chemotherapy, functional impairment, overall QL, and HADS anxiety and depression are listed in Table 4. In general, patients experienced similar levels of QL across the two treatment groups except that tingling of hands or feet and functional impairment were worse for ICE-V at 6 months; and lack of appetite, feeling tense, and sore mouth were worse for C at 3 months. During the first 3 months, there was a significant improvement from baseline in terms of the proportion of patients with moderate/severe symptoms for both treatment groups for cough, shortness of breath, pain, difficulty sleeping, tension, worrying, and HADS anxiety (all P < .0001), whereas adverse effects were as expected. Decreased sexual interest significantly increased from baseline (P < .0001), whereas tiredness and lack of energy were refractory to treatment (P = .50 and P = .47, respectively). Statistically significant between-treatment changes from baseline to 3 months, all in favor of ICE-V, were observed for lack of appetite (decreased, P < .0001), HADS depression (decreased, P < .0001), and overall QL (improved, P < .0001). Data were limited at 6 months due to patient attrition and reduced compliance, so that differences were not explored.
Tumor Response Of the 189 ICE-V and 183 C patients assessable, 75 and 67 patients, respectively, had a complete response during protocol treatment, and 82 and 80 patients, respectively, had a partial response, producing total response rates of 83% in the ICE-V and 80% in the C group (P = .65).
Survival
This randomized trial has shown that a regimen of ICE-V administered every 4 weeks significantly prolongs survival compared with standard, mainly nonplatinum-based chemotherapy administered every 3 weeks in the treatment of patients with SCLC and good performance status. Moreover, this survival advantage was also associated with some QL benefits. Perhaps counterintuitively, the four-drug combination regimen (ICE-V) was well tolerated, with 75% of patients receiving four or more cycles, and compared with the standard treatment group, the increased levels of numbness were balanced by reductions in sore mouth, lack of appetite, and feeling tense. The main detrimental effect of the ICE-V regimen was the increased rate of septicemia (7% in the C group and 15% in the ICE-V group), although this was generally well managed, and the same number of treatment-related deaths was reported in both groups. The acceptability of this regimen is likely to be explained in part by the use of carboplatin rather than cisplatin, as the latter is nephrotoxic, neurotoxic, and ototoxic. There was an unexpected suggestion of more benefit with ICE-V with increasing age, a possible explanation of which might be a detrimental cardiopulmonary effect of the doxorubicin used in the CDE regimen. The recommendation for patients receiving ICE-V was that when a cycle could not be administered at full dose and on time, a policy of delaying and treating at full dose when feasible should be adopted rather than reducing the doses. The rationale for such a policy was to maintain the dose-intensity.4,9 The expectation was that in the standard chemotherapy group, some patients would also have cycles delayed, whereas others had cycles administered on time but with drug doses reduced or omitted. However, similar proportions of cycles were delayed in both treatment arms, and thus it is unclear what effect this policy had on the trial outcomes. The benefit seen in the current trial with a platinum-based regimen is echoed by two retrospective reviews, a meta-analysis based on published data, and one more recent trial. A review of SCLC patients treated at the US National Cancer Institute suggested a modest survival benefit for PE in LS patients,19 and analyses of ES SCLC patients in North American trials and the Surveillance, Epidemiology, and End Results database suggested improvements in survival as a result of the use of cisplatin.20 In addition, the meta-analysis21 indicated a small survival benefit (odds ratio at 1 year, 0.80; 95% CI, 0.69 to 0.93) with the use of cisplatin-based regimens. A Norwegian randomized trial22 conducted after the meta-analysis also demonstrated survival improvement with PE over an anthracycline regimen (cyclophosphamide, epirubicin, and vincristine), with a median survival of 10.2 months for PE compared with 7.8 months in the CEV arm (P = .0004). However, this survival benefit was only observed in LS (P = .0001) and not in ES patients (P = .21). Two three-arm trials,23,24 comparing PE, CAV, and alternating CAV/PE, also failed to show a survival advantage for PE compared with CAV in ES patients. This contrasts with the current trial, in which there was no evidence that ES patients did not attain the same relative survival benefit with ICE-V, although the number of ES patients was rather small. Treatment for patients with SCLC and a good PS might be improved by adding one or more drugs to platinum/etoposide, dose intensification, the use of concurrent chemoradiotherapy, or the use of new drugs. Generally, the addition of other drugs to PE has not improved outcome, although in a French randomized trial in ES patients25 the addition of epirubicin and cyclophosphamide to PE did improve survival (median survival, 10.5 v 9.5 months; 1-year survival, 40% v 29%; P = .0067). However, this result has not been replicated in two other trials in which paclitaxel was added to PE.26,27 There are a number of ways of increasing the total dose and the dose-intensity of chemotherapy: increasing the number of cycles, increasing the dose per cycle, decreasing the interval between cycles, or combinations of these. A meta-analysis of the published literature28 suggested that all of these strategies are relevant for improving survival, although not all individual trials show this pattern.29 Although there are proven survival benefits in adding radiotherapy to chemotherapy for LS SCLC patients,30,31 the optimum timing of radiotherapy is unclear. A recent meta-analysis of fully published trials32 indicated a benefit for early thoracic radiotherapy, particularly in conjunction with PE chemotherapy and with hyperfractionated radiotherapy. However, a trial repeating the design of an earlier trial (which showed a significant survival advantage for early radiotherapy33) reported no difference.34 The result of adding this trial to the meta-analysis is that now no overall survival benefit is seen with early radiotherapy, although the significant benefits in favor of early radiotherapy in the subgroups of platinum-based chemotherapy and hyperfractionated radiotherapy trials remain.32 A Japanese trial35 comparing concurrent chemoradiotherapy (PE with 45 Gy administered in twice-daily fractions starting with cycle 1 every 4 weeks) and sequential treatment 4 (cycles of PE administered every 3 weeks with the same radiotherapy administered after cycle 4) showed a much improved median survival with concurrent treatment (27.2 v 19.7 months) although with only 231 patients, this did not translate into a statistically significant difference. However, phase I studies are now exploring the maximum-tolerated doses of radiotherapy that can be administered concurrently with PE, and total doses of 61.236 and 70 Gy37 have been reported. The emergence of newer cytotoxic drugs may also offer opportunities to improve the outlook of patients with SCLC. For example, a trial of irinotecan and cisplatin38 was stopped after the accrual of 154 patients because the survival in the irinotecan/cisplatin arm was statistically superior, but this result has yet to be duplicated.39 Although all the above strategies are worth pursuing, the future probably lies with biologically targeted agents; SCLC exhibits numerous molecular abnormalities, including neuropeptide, gastrin-releasing peptide, CD117, and vascular endothelial growth factor expression, which may be exploitable.40 However, as long as absolute survival advantages remain small, the need to show comparable QL benefits remains important. In the current trial, both treatment arms showed substantial palliation of key symptoms, and improvement in anxiety during treatment. Of note, the improvement in overall QL was reported as superior with the ICE-V regimen, although factors explaining this result cannot be ascertained fully from the data. The C arm was inferior with respect to depression ratings and toxicity, which may contribute to the difference. Both regimens were well tolerated with respect to more severe levels of nausea and vomiting, but fatigue was unchanged and functional impairment increased. The precise clinical impact of these differences is difficult to determine, but it is important to discuss the balance of survival, potential QL benefits, and toxicities with patients during treatment decision making. In conclusion, this trial confirms that patients with SCLC and good performance status should be treated with a platinum-based chemotherapy regimen. The ICE-V regimen has been shown in the present trial to provide a survival advantage over currently accepted standard regimens, without QL penalties, despite an increased but manageable level of toxicity, and is therefore worthy of additional investigation.
The following are members of the Medical Research Council (MRC) Lung Cancer Working Party: M.G. Bond, P.I. Clark, C.K. Connolly, D.J Girling, P.S. Hasleton, P. Hopwood, F.R. Macbeth, R. Milroy, K. Moghissi, M.D. Peake, W. Qian, R.J. Sambrook, M.I. Saunders, I.E. Smith (Chairman), R.J. Stephens, N. Thatcher (Chairman until October 1997), D.C.T. Watson, and R.J. White. Principal investigator: N. Thatcher; quality of life advisor: P. Hopwood; MRC clinical coordinator: D.J. Girling; MRC data management: R.J. Sambrook, H. Brook, D. Lobban, A. Hodson and R. Owens; MRC data analysis: A. Bailey, R.J. Stephens, W. Qian, M.K.B. Parmar. Independent data monitoring committee: Dr. M.H. Cullen (Chairman), Dr. J. Slattery and Dr. J. Tobias. Trial Steering Committee: Professor H. Kitchener (Chairman), Professor T. Maughan and Professor M. Seymour. Trial collaborators and coauthors: M.C. Nicolson (Aberdeen Royal Infirmary, Aberdeen); S.M. Crawford (Airedale General Hospital, Keighley); L.F. Ng (Birmingham Heartlands Hospital, Birmingham); D. Varghese, D.R.T. Shepherd (Belfast City Hospital, Belfast); L.F. Evans (Blackpool Victoria Hospital, Blackpool); N. Thatcher, H. Anderson (Christie Hospital and Wythenshawe Hospital, Manchester); P.I. Clark, D.B. Smith, S. O’Reilly, E. Marshall (Clatterbridge Hospital, Bebington); M. Snee (Cookridge Hospital, Leeds); C.P. Bredin (Cork University Hospital, Cork); K. Connolly, E.N. Evans, P. Chakraborti (Darlington Memorial Hospital, Darlington); A. Peacock, B. Stack (Gartnavel General Hospital, Glasgow); J.K. Joffe, B.A. Crosse (Huddersfield Royal Infirmary, Huddersfield); J.S. Morgan (Ipswich Hospital, Ipswich); S. Hima (Jersey General Hospital, St Helier); F.J.F. Madden, K. J. O’Byrne (Leicester Royal Infirmary, Leicester); M.E.R. O’Brien (Maidstone Hospital, Maidstone); G. Anderson (Newport Chest Clinic, Newport); E. Rankin, M.S. Highley (Ninewells Hospital, Dundee); C.H. MacMillan, D.P. Levy, C. Elwell (Northampton General Hospital, Northampton); J.A. Carmichael, P.J. Woll (Nottingham City Hospital, Nottingham); K. McAdam (Peterborough District Hospital, Peterborough); G. Skailes (Royal Preston Hospital, Preston); P.M.W. Johnson (Royal South Hants Hospital and Southampton General Hospital, Southampton); P. Selby, M. Leahy (St James’ University Hospital, Leeds); E. Neville, D. Evans, S.A. Evans, A.J. Chauhan, T.J.G. Gulliford (St Mary’s Hospital, Portsmouth); R. Milroy (Stobhill Hospital, Glasgow); R.N. Harrison, N. Leitch (University Hospital of North Tees, Stockton on Tees); D. MacIntyre (Victoria Infirmary, Glasgow); M. Hocking (Walsgrave Hospital, Coventry); P. Lorigan, M. Hatton, P. Kirkbride (Weston Park Hospitial, Sheffield); A. Gregor, A. Price (Western General Hospital, Edinburgh); R.D. Jones, D. Dunlop, A. Armour (Western Infirmary, Glasgow). Local coordinators: L. Barnett (Aberdeen Royal Infirmary, Aberdeen); J. Peace (Airedale General Hospital, Keighley); J. Price, L. Brewer (Birmingham Heartlands Hospital, Birmingham); A. Morrison (Belfast City Hospital, Belfast); H. Williams, L. Lomax, L. Ashcroft, C. Berrisford (Christie Hospital and Wythenshawe Hospital, Manchester); K. Hannigan, C. Ball, J. Skilling, D. Merritt, J. Reilly (Clatterbridge Hospital, Bebington); J. White (Cookridge Hospital; Leeds); A. Arya (Cork University Hospital, Cork); S. Alcock (Darlington Memorial Hospital, Darlington); S. Miller (Derbyshire Royal Infirmary, Derby); M. Cannon, C. Wheelhouse (Huddersfield Royal Infirmary, Huddersfield); P. Taylor-Neale (Ipswich Hospital, Ipswich); D. Hammond, L. Furber, C. Mason (Leicester Royal Infirmary, Leicester); R. Bass, C. Ryan (Maidstone Hospital, Maidstone); D. Forbes, B. Massie (Ninewells Hospital, Dundee); N. Perry (Northampton General Hospital, Northampton); J. Berridge, C. Gooch (Nottingham City Hospital, Nottingham); L. Bath (Peterborough District Hospital, Peterborough); J. Wardle, T. Parkinson (Royal Preston Hospital, Preston); M. Fay, S. Dixon, J. Dobbyn (Royal South Hants Hospital and Southampton General Hospital, Southampton); V. Wilson (St James’ University Hospital, Leeds); G. Dear, A. Snow, S. Roberts (St Mary’s Hospital, Portsmouth); J. Graham (Stobhill Hospital, Glasgow); D. Halliman, E. Simmons (Walsgrave Hospital, Coventry); F. Peet, K. Fiddes (Western General Hospital, Edinburgh); C. Lawless (Western Infirmary, Glasgow); S. Browne, K. Campbell (Weston Park Hospital, Sheffield). The Appendix is included in the full-text version of this article, available online at www.JCO.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
We thank the patients who participated in this study.
Supported by the British Medical Research Council. Asta Medica provided partial funding for data collection. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test for interaction or trend was implemented in predefined exploratory analyses to assess the differences of the relative benefits of ICE-V in different subgroups of patients. The best tumor response achieved during treatment was compared using the Mann-Whitney test. The standard 
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